RESUMO
Ataxia-telangiectasia mutated (ATM) is a cell cycle checkpoint kinase that upon activation by DNA damage leads to cell cycle arrest and DNA repair or apoptosis. The absence of Atm or the occurrence of loss-of-function mutations in Atm predisposes to tumorigenesis. MAPK7 has been implicated in numerous types of cancer with pro-survival and pro-growth roles in tumor cells, but its functional relation with tumor suppressors is not clear. In this study, we show that absence of MAPK7 delays death due to spontaneous tumor development in Atm-/- mice. Compared with Atm-/- thymocytes, Mapk7-/-Atm-/- thymocytes exhibited an improved response to DNA damage (increased phosphorylation of H2AX) and a restored apoptotic response after treatment of mice with ionizing radiation. These findings define an antagonistic function of ATM and MAPK7 in the thymocyte response to DNA damage, and suggest that the lack of MAPK7 inhibits thymic lymphoma growth in Atm-/- mice by partially restoring the DNA damage response in thymocytes.
Assuntos
Proteínas Mutadas de Ataxia Telangiectasia/genética , Transformação Celular Neoplásica/genética , Proteína Quinase 7 Ativada por Mitógeno/genética , Animais , Proteínas Mutadas de Ataxia Telangiectasia/deficiência , Linfócitos B/metabolismo , Linfócitos B/patologia , Ciclo Celular/genética , Transformação Celular Neoplásica/metabolismo , Dano ao DNA/genética , Dano ao DNA/efeitos da radiação , Deleção de Genes , Expressão Gênica , Hematopoese/genética , Histonas/metabolismo , Camundongos , Camundongos Knockout , Proteína Quinase 7 Ativada por Mitógeno/metabolismo , Mutação , Fosforilação , Radiação Ionizante , Transdução de Sinais , Timócitos/metabolismo , Timócitos/patologiaRESUMO
An adequate supply of nucleotides is essential for accurate DNA replication, and inappropriate deoxyribonucleotide triphosphate (dNTP) concentrations can lead to replication stress, a common source of DNA damage, genomic instability and tumourigenesis. Here, we provide evidence that Erk5 is necessary for correct nucleotide supply during erythroid development. Mice with Erk5 knockout in the haematopoietic lineage showed impaired erythroid development in bone marrow, accompanied by altered dNTP levels and increased DNA mutagenesis in erythroid progenitors as detected by exome sequencing. Moreover, Erk5-depleted leukemic Jurkat cells presented a marked sensitivity to thymidine-induced S phase stalling, as evidenced by increased H2AX phosphorylation and apoptosis. The increase in thymidine sensitivity correlated with a higher dTTP/dCTP ratio. These results indicate that Erk5 is necessary to maintain the balance of nucleotide levels, thus preventing dNTP misincorporation and DNA damage in proliferative erythroid progenitors and leukemic Jurkat T cells.
